Pump dysfunction and a dilated, relatively thin-walled ventricle typically characterize heart failure. Excessive cardiac myocyte lengthening is largely responsible for chamber dilatation in heart failure due to hypertension. As chamber dilatation and myocyte lengthening progress, the absence of growth in myocyte cross-sectional area impairs wall thickening and leads to elevated wall stress. Remodeling of LV myocyte shape in human hypertensives progressing to failure is similar to that in Spontaneously Hypertensive Heart Failure (SHHF) rats, which will be used in these studies. New data from SHHF rats show that Angiotensin type 1 (AT-1) receptor blockade reverses myocyte length and cross-sectional area back to normal or near normal values even when given just prior to the onset of heart failure. Hydralazine also normalized blood pressure, but there was no regression of myocyte hypertrophy. Hydralazine did, however, arrest progression of myocyte lengthening. The objective of this proposal is to determine the relative contributions of load and AT1 signaling in the remodeling of LV myocyte shape in the progression to failure. These two drugs and AT1 antisense therapy will be used in various combinations as tools to perturb the pathological growth process of LV myocytes in SHHF rats. This will allow investigators to determine the relative role of load (e.g. via membrane integrins and cytoskeleton) and signaling through the AT1 receptor in growth and regression of myocyte dimensions. At terminal experiments, LV hemodynamics, chamber dimensions (echos), and wall stress will be determined. Whole tissue and isolated myocytes will be used for determination of cellular dimensions and confocal analysis of membrane integrins, cytoskeleton, and G-protein signaling molecules. Specific aims will examine the role of mechanical signaling and signaling through Angiotensin receptors in growth and regression of myocyte length and cross-sectional area. These studies will fill a critical void in our understanding of the cellular and molecular mechanisms underlying a key pathophysiologic cellular alteration that contributes to, or may actually cause, heart failure.